ABSTRACT Diabetes mellitus is characterized by an inability of pancreatic ? cells to produce and secrete sufficient insulin to meet the needs of the body. While the mechanisms regulating insulin secretion are well understood, less is known about the processing of proinsulin to mature insulin in pancreatic ? cells. In humans, elevated circulating proinsulin is associated with impaired proinsulin processing and the development of type 2 diabetes (T2D). We have discovered that mice with a targeted deletion of the iron regulatory protein 2 (Irp2) gene, which leads to a depletion of intracellular iron content, develop hyperglycemia, glucose intolerance and impaired glucose- stimulated insulin secretion from pancreatic ? cells. Irp2-/- mice display increased pancreatic proinsulin content, decreased insulin content and reduced insulin secretion, suggesting that dysregulation of intracellular iron homeostasis causes a defect in proinsulin processing in ? cells. We propose that the depletion of intracellular iron in ? cells impairs mitochondrial function and endoplasmic reticulum (ER) homeostasis, leading to defective proinsulin processing. We plan to identify specific functional changes in these pathways in Irp2 deficient ? cells that will give new insight into molecular mechanisms that can be targeted in ? cell dysfunction.